Process for preparing o-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides

ABSTRACT

The present invention relates to a novel process for preparing O-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides of formula (I) by reacting a carboxamide oxime of formula (II) wherein R 1  is as specified above with reactive 3-amino-2-hydroxy-propane derivative diazotizing the O-substituted carboxamide oxime thus obtained with sodium nitrite in the presence of hydrogen halide, decomposing the diazonium salt and if desired, separating the optically active enantiomers and/or reacting the resulting base with an organic or mineral acid wherein the carboxamide oxime of formula (II) is reacted with a 3-hydroxy azetidinium salt of formula (III) wherein R 2  and R 3  are a defined above and Y −  is a salt forming anion, in a lower alcoholic, preferably ethanolic medium optionally containing water and made alkaline with an alkali hydroxide, and before diazotizing the O-substituted carboxamide oxime intermediate obtained, the reaction mixture is neutralised and the organic solvent is removed. The process according to the invention provides the compounds of formula (I) with higher yield compared to the prior art processes.

TECHNICAL FIELD

The present invention relates to a novel process for preparingO-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides of the formula (I)wherein

R¹ is phenyl, pyridyl or thienyl or substituted phenyl, wherein the oneor more substituent(s) may be halo and/or haloalkyl and/or nitro,

X is halo,

R² and R³ are independently from each other straight or branched loweralkyl or

R² and R³ together with the nitrogen connecting thereto form a saturated5 to 7-membered heterocyclic group which may contain additional heteroatom and may be substituted.

The invention also relates to a process for preparing the acid additionsalts and optically active forms of the above compounds.

BACKGROUND ART

O-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides of the generalformula (I) are well known as active substances in the treatment ofpathological changes in the vascular system connected with diabetesmellitus, especially with diabetic angiopathy. These compounds areparticularly described e.g. WO-A-90/04584.

O-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides of the generalformula (I) can be prepared in many different ways some of them beingalso described in the WO-A-90/04584.

Although the known synthesis routes for manufacture are suitable allowthe preparation of the compounds of formula (I), they are not sufficientfor the preparation of the said compounds in industrial scale. Thedisadvantage thereof is that they need reagents which are difficult tohandle or prepare or comprise unfavourable reactions withnon-satisfactory yields due to the possibility of side reactions. Theurging need for the compounds of formula (I) requires a novel processwhich is secure, has a satisfactory yield and can be carried out underindustrial conditions.

DISCLOSURE OF INVENTION

The present invention aims to provide a process for preparingO-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides in industrialscale.

The present invention provides an industrially applicable process forpreparing the compounds of the formula (I) by

i) reacting an amidoxime compound of the formula (II) with a3-hydroxy-azetidinium salt of the formula (III) wherein

R² and R³ have the meaning as specified above and

Y⁻ is a salt forming anion in a basic-alcoholic medium,

ii) neutralizing the mixture and removing the organic solvent,

iii) reacting the residue with sodium nitrite in aqueous medium in thepresence of hydrochloric acid

iv) decomposing the diazonium salt thus obtained and

v) isolating the crude product of the formula (I) from the mixture.

Reactions of amidoxime compounds of the formula II and suitablysubstituted 3-amino-2-hydroxy-propane derivates (usually 1-halo- or1,2-epoxy derivates) are described e.g. in GB Patent No. 1.582.029.However, the 3-hydroxy azetidinium salts of the formula (III) are moresuitable reagents than the 1-halo- or 1,2-epoxi derivates used in theknown reactions. Namely, compounds of the formula (III) are solidmaterials which can easily be prepared, isolated and stored unlike thereagents materials. The use thereof became known from WO-A-90/08131, butin the process described therein neither these nor the other tworeagents are directly reacted with the compounds of the formula (II),but with an amidoxime complex prepared therefrom with alkali hydroxideor alkali and dimethyl formamide alcoholate or1,3-dimethyl-2-imidazolidinone in a medium containing dimethylformamide. Thus, O-substituted amidoxime derivatives were isolatedwhich, however appear only as non-isolated intermediates in the reactionsequence according to the present invention.

Based on our observations efforts were made to eliminate thetechnologically difficult complex forming from the process and to avoidthe use of dimethyl formamide as solvent. Dimethyl formamide ishazardous for health as it causes cancer, furthermore it is difficult toregenerate and purify and extremely difficult to make water-free. Thisis especially important as dimethyl formamide impurity must be minimizedas pointed out in WO-A-90/08131. Moreover, it is preferable that thesolvent contains only very small quantity of water, practically lessthan 1% to achieve a proper yield. An additional disadvantage of the useof dimethyl formamide is that it decomposes when exposed to light thusbecoming contaminated by the toxic compounds envolved. It has been foundthat the reaction can safely and easily be carried out by redacting thecompounds of the formulae (II) and (III) directly in a basic alcoholicmedium which may also contain water. In respect of the outcome of thesynthesis it is very useful that the O-substituted carboxamide oximeintermediate is not isolated from the reaction mixture, but directlyreacted further after neutralizing the mixture and removing the organicsolvent. It has also been found that the side products formed during thecontracted steps can all be removed by one suitable isolation step andthus, the synthesis is appropriate for manufacturing the product in thedesired purity.

Based on these observations, the invention provides a process forpreparing compounds of the formula (I), wherein

R¹ is phenyl, pyridyl or thienyl or substituted phenyl, wherein the oneor more

X is halo,

R² and R³ are independently from each other straight or branched loweralkyl or

R² and R³ together with the nitrogen connecting thereto form a 5 to7-membered saturated heterocyclic group which may contain additionalhetero atom and may be substituted,

and the acid addition salts and optically active forms thereof byreacting a carboxamide oxime of the formula (II) wherein the meaning ofR¹ is as specified above with a reactive 3-amino-2-hydroxy-propanederivate, diazotizing the resulting O-substituted carboxamide oxime withsodium nitrite in the presence of hydrohalide, decomposing the diazoniumsalt, isolating the product obtained and, if desired, separating theoptically acive enantiomers and/or reacting the resulting base with anorganic or mineral acid; which comprises reacting the carboxamide oximeof the formula (II) with a 3-hydroxy acetidinium salt of the formula(III) wherein R² and R³ have the meaning as specified above and Y⁻ is asalt forming anion in a C₁₋₄ alcoholic preferably ethanolic medium madealkaline with an alkali hydroxide, the said medium optionally containingwater while neutralizing the reaction mixture and removing the organicsolvent therefrom before diazotizing the resulting O-substitutedcarboxamide oxime intermediate.

BEST MODE FOR CARRYING OUT THE INVENTION

A preferred mode of carrying out the process according to the inventionis as follows:

The carboxamid oxime of the formula (II) and the 3-hydroxy azetid niumsalt of the formula (III) are reacted at stoichiometric ratio, however,it may be advantageous to apply the compound of the formula (III) in aslight excess. The reaction can be carried out with any order ofaddition of the reagents, preferably the compound of the formula (II) isadded to the basic-alcoholic solution of the compound of the formula(III). As solvent preferably a C₁₋₄ alkanol, preferably ethanol is usedand the reaction is carried out preferably with heating, most preferablyat the boiling point of the solvent. After termination of the reaction,the mixture is cooled and neutralized with a mineral pressure. Afterremoving the solvent the reaction mixture is diluted with water, theconcentrated hydrochloric acid necessary for diazotizing is added,cooled to the diazotizing temperature and is diazotized by the additionof the sodium nitrite under cooling at a temperature of 0 to +5° C. Thediazonium salt decomposes in situ into the correspondinghydroximoyl-halide derivative. To isolate the crude product, thereaction mixture is made alkaline with an inorganic alkali compound,extracted with an organic solvent non-miscible with water, preferablyethyl acetate, the extract is dried and concentrated, or directly anacid addition salt is formed from the product by adding a suitable acidto the mixture and separating the acid addition salt by filtration. Thecrude product can be purified by recrystallization or by any other wayknown in the art.

By using the above process, a properly pure product can be prepared withan economically satisfactory yield.

The advantage of the present invention lies in the fact that it makespossible to produce O-(3-amino-2-hydroxy-propyl)-hydroxime acid halidesby a safe and simple method also under industrial conditions.

The invention is further illustrated in the following examples:

EXAMPLE 1

N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyrydine-carboximidoylchloride (Z)-2-butenedioate

50.4 kg 2-hydroxy-4-azoniaspiro-[3,5]-nonane chloride was dissolved inand 28 l of water under stirring. To the solution 11.4 kg sodiumhydroxide was added and the resulting milk-like mixture was stirred foran additional hour. While stirring, 420 l of ethanol and 35 kg3-pyrydine-carboxamide oxime were added thereto and the mixture washeated under reflux for 1.5 hours followed by cooling the reactionmixture. 270-290 l of alcohol were distilled off and 110 l of deionizedwater and 45.5 l of concentrated hydrochloric acid were added followedby distilling off the remaining ethanol. To the oily residue 160 l ofconcentrated hydrochloric acid was added under cooling so that thetemperature remained under 30° C. The solution was then cooled to 0° C.and for the diazotization a mixture of 17.7 kg sodium nitrite and 60 lof deionized water was added under permanent stirring and cooling whilemaintaining the temperature of the reaction mixture between 0 and +5° C.After the addition, the mixture was stirred for an additional hour atthis temperature and for the decomposition of the nitrite excess 1.5 kgurea was added. After full decomposition of the nitrite (appr. 1.5hours) to the reaction mixture 350 l ethyl acetate was added followed byalkalifying by the addition of 150-200 l concentrated sodium hydroxideunder stirring and intensive cooling. The layers were separated, theorganic phase washed with 2×70 l of water and dried over 15 kg anhydrousNa₂SO₄. The drying agent was filtered off, washed with 20 l ethylacetate, the organic layers combined and the quantity of theN-[2-hydroxy-3-(piperidine-1-yl)-propoxy-3-pyrydine-carboximidoylchloride base was determined. Maleic acid in calculated amount (21-22kg) was added and the mixture was stirred for 4 hours. The product wasseparated in centrifuge, washed with 30 l acetone and the resultingcrude product was dissolved in 70 l warm acetone and recrystallized. Theproduct was separated in centrifuge and washed with 30 l acetone. Afterrecrystallization, 50-55 kgN-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-piridine-carboximidoylchloride (Z)-2-butenedioate (1:1) was obtained as pink beige crystals.(m.p. 123-124° C., acetone, yield: 53%).

IR (v, KBr/cm⁻¹): 3350, 2941, 1580, 1480, 1350, 1022, 982, 867, 702.

¹H-NMR (250 MHz, DMSO-d₆; ref.: DMSO-d₆=2.5δ(ppm): 9.00 (1H, s); 8.74(1H, d); 8.18 (1H, d), 7.56(1H, dd); 6.03 (2H, s); 5.85-6.00 (1H, s/br);4.21-4.37 (3H, m); 3.2-3.33 (2H, m); 2.49-2.55 (4H, m); 1.54-1.77 (6H,m). ¹³ ^(C-NMR ()63 MHz, solvent: DMSO-d₆; ref.: DMSO-d₆=39.3.δ(ppm):167.0 (COOH); 151.4, 127.9, 134.3, 123.5. 147.2 (pyrydine 2-3-4-5-6);135.4 (CH═CH); 134.9 C/Cl/═NO); 77.2 (NOCH₂); 63.5 (CHOH, 58.3) (NCH₂);52.9, 22.1, 21.2 (piperydine).

According to Example 1 the following compounds were prepared:

EXAMPLE 2

N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-benzimidoyl chloridehydrochloride

(m.p.: 140-144° C., isopropanol, yield: 66%) IR (KBr): 3234, 2951, 1504,1448, 1389, 1289, 1119, 1059, 972, 768, 690.

EXAMPLE 3

N-{2-hydroxy-3-[-(4-methyl)-piperazinyl]-propoxy}-3-piridine-carboximidoylchloride (Z)-2-butenedioate (1:2)

(m.p.: 174-175° C., ethanol, yield: 48%) IR (KBr): 3207, 1693, 1578,1456, 1358, 1304, 1020, 974, 864, 702.

EXAMPLE 4

N-[2-hydroxy-3-(diethylamino)-propoxy]-3-piridine-carboximidoyl chloridehydrochloride

(m.p.: 118-119° C., acetone, yield: 67%) IR (KBr): 3425, 3289, 2951,2667, 1818, 1443, 1337, 1238, 1178, 1115, 1078, 1049, 997, 910, 804,781, 696, 683 cm⁻¹

EXAMPLE 5

N-[2-hydroxy-3-(4-morpholinyl)-propoxy]-3-piridine-carboximidoylchloride (Z)-2-butenedioate

(m.p.: 137-138° C., isopropanol, yield: 52%) IR (KBr): 3310, 1580, 1483,1464, 1443, 1354, 1072, 1024, 982

EXAMPLE 6

N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-2-tiophene-carboximidoylchloride hydrochloride

(m.p.: 115-123° C., isopropanol-hexane, yield: 38%)

¹H-NMR (250 MHz, DMSO-d₆; ref.: DMSO-d₆=2.5δ(ppm): 10.2 (1H, s/br);7.81, 7.63, 7.20 (1H, 1H, 1H, d, d, dd); 5.98 (1H, s/b); 4.42 (1H, s/b),4.35 (2H, d); 3.60-2.90 (6H, m); 1.95-1.60 (4H, m); 1.45-1.20 (2H, m).

¹³C-NMR (63 MHz DMSO-d₆; ref.: DMSO-d₆=39.3δ(ppm): 133.8 [C(Cl)═N];132.1, 130.3, 130.1. 127.6 (tiophene 3-2-5-4); 76.8 (NOCH₂); 63.2(CHOH); 58.5 (CH₂N); 53.3, 51.8 (piperidine 2×NCH₂) 22.0, 21.9, 21.0(piperidine 3×CH₂).

EXAMPLE 7

N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-2-trifluoromethyl benzimidoylchloride hydrochloride

(m.p.: 119-123° C., ethylacetate, yield: 30%) IR (KBr): 3366, 2937,2854; 2737, 2673, 2538, 1616, 1570, 1439, 1404, 1337, 1290, 1236, 1199,1165, 1129, 1101, 1074, 1030, 984, 972, 933, 901, 829, 804, 788, 717,699, 685, 646 cm⁻¹.

EXAMPLE 8

N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-2′-nitrobenzimidoyl chloridehydrochloride

(m.p.: 159-162° C., isopropanol, yield: 43%) IR (KBr): 3298, 2983, 2932,2746, 1593, 1574, 1535, 1445, 1391, 1354, 1317, 1288 1242, 1198, 1117,1092, 1069, 1020, 968, 947, 914, 852, 793, 756, 708, 577 cm³¹.

EXAMPLE 9

(+) N-[2-hydroxy-3-(1-piperidine-1-yl)-propoxy]-3-piridine-carboximidoylchloride (Z)-2-butenedioate (1:1)

2-hydroxy-4-azoniaspiro[3,5]nonane chloride and 3-piridine-carboxamideoxime were reacted according to Example 1 following the reaction stepsup to separating theN-[2-hydroxy-3-(1-piperidine-1-yl)-propoxy]-3-piridine-carboximidoylchloride with ethyl acetate. 15 g (50 mmole)N-[2-hydroxy-3-(1-piperidin-1-yl)-propoxy]-3-piridine-carboximidoyl-chloridein ethyl acetate was added dropwise to a mixed anhydride prepared from13.52 g (50 mmole) N-(t-butoxycarbonyl)-L-phenylalanine and 5.0 ml ethylchloroformiate in dichlorometane by a method known per se and themixture was stirred for an hour at room temperature. To isolate theester thus obtained the solution was extracted with 2×200 ml aqueousacetic acid solution (10%) and 1×200 ml water, the organic layer wasdried over anhydrous Na₂SO₄ and concentrated. The oily residue wasdissolved in 140 ml acetone and to the solution 3.0 g maleic acid wasadded. Thus, 5.2 g (7.8 mmole, 16%)(−)N-[2-(N′-BOC-/L/-phenylalanyloxy)-3-(1-piperidinyl)-propoxy]-3-piridine-carboximidoylchloride (Z)-2-butenedioate (1:1) salt (m.p.: 146.5-148° C.) wasobtained.

5.2 g of the salt prepared as above was boiled in methanol for 1 hour.The solution was distilled to dryness and the residue was crystallizedfrom 50 ml ethyl acetate giving 3.18 g (98%) (+)N-[2-hydroxy-3-(1-piperidin-1-yl)-propoxy]-3-piridine-carboximidoylchloride (Z)-2-butenedioate (1:1) salt (m.p.: 136-137° C.). The IR andNMR spectrum of the compound corresponded to those of the racemiccompound. According to chiral shift spectroscopy the compound was ahomogenous enantiomer. The (−) isomer could be prepared in an analogousway, but using N-(t-butoxycarbonyl)/D/-phenylalanine as reagent.

The method according to the invention was compared with the methoddescribed in the prior art mentioned above. 3-piridine-carboxamide oximewas reacted with 3-piperidino-2-hydroxy-1-chloropropane preparedaccording to the method described in GB Patent 1.582.029 in absolutealcoholic medium. After termination of the reaction the solution wasmade alkaline, the product was extracted with benzene and from the basedihydrochloride was formed with gaseous hydrochloric acid. TheO-(3-piperidino-2-hydroxy-1-propyl)-3-piridine-carboxamide oximehydrochloride thus obtained was diazotized according to the methoddescribed in WO-A-90/04584, the diazonium salt was decomposed and theresulting product was reacted with maleic acid giving the productaccording to example 1. The final yield of the process based on thestarting product was 38% while the same in Example 1 was 53%, whichraised up to 60% during commercial production.

It can be established that the process according to the inventionprovides the compounds of the formula (I) with a higher yield comparedto the prior art processes. A further advantage of the process accordingto the invention is the possibility to spare solvent. For preparing 1 kgproduct according to the process described in the present invention only17 kg solvent was needed while the same according to the formerly knownprocesses amounted to 40 kg. A further advantage of the processaccording to the invention in the industrial scale is that thetechnology time needed for the preparation of the compounds of theformula (I) is shorter. To produce 1 batch of the product related to 3m³ reactor volume according to the invention needed 4 consecutive shiftswhile the prior art processes needed 8 shifts.

Summarized, the process according to the present invention provides amethod to prepare the O-(3-amino-2-hydroxy-propyl)-hydroximic acidhalides with a higher yield and with substantially reduced technologicalcosts than the processes previously known.

What is claimed is:
 1. Process for preparingO-(3-amino-2-hydroxy-propyl)-hydroximic acid halides of the formula Iwherein R¹ is phenyl, or pyridyl or thienyl or substituted phenyl,wherein the one or more substituent(s) may be halo and/or haloalkyland/or nitro, X is halo, R² and R³ are independently from each otherstraight or branched lower alkyl or R² and R³ together with the nitrogenconnecting thereto form a 5 to 7-membered saturated heterocyclic groupwhich may contain additional hetero atom and may be substituted, and theacid addition salts and optically active forms thereof by reacting acarboxamide oxime of the formula (II) wherein R¹ is as specified abovewith reactive 3-amino-2-hydroxy-propane derivative, diazotizing theO-substituted carboxamide oxime thus obtained with sodium nitrite in thepresence of hydrogen halide, decomposing the diazonium salt and ifdesired, separating the optically acive enantiomers and/or reacting theresulting base with an organic or mineral acid, characterized in thatthe carboxamide oxime of the formula (II) is reacted with a 3-hydroxyazetidinium salt of the formula (III) wherein R² and R³ are as definedabove and Y⁻ is a salt forming anion in a C₁₋₄ alcoholic, mediumoptionally containing water and made alkaline with an alkali hydroxide,and before diazotizing the O-substituted carboxamide oxime intermediateobtained, the reaction mixture is neutralized and the organic solvent isremoved.
 2. The process of claim 1 characterized by using ethanol asC₁₋₄ alcohol.